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ESA1 - Physiology and Pharmacology > Pharmacodynamics > Flashcards

Pharmacodynamics Flashcards

1
Q

How do drugs exert effects?

A

By binding to a target - usually a protein

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2
Q

What is an example of a b2-adrenoceptor agonist?

A

Salmeterol - used in asthma treatment

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3
Q

What does adalimumab treat?

A

Rheumatoid arthritis

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4
Q

What is critical in determining drug action?

A

Concentration of drug molecules around receptors

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5
Q

What is pharmacodynamics?

A

Study of how drug effects the body

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6
Q

What is a ligand?

A

A molecule/ion that binds to another molecule (usually a receptor)

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7
Q

What is the difference between affinity and efficacy?

A 
Affinity = how easily it binds
Efficacy = how effective it is when bound
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8
Q

What is an agonist?

A

A substance which initiates a physiological response when combined with a receptor.

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9
Q

What is an antagonist?

A

A substance which interferes with or inhibits the physiological action of another.

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10
Q

What are partial agonists?

A

Drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist.

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11
Q

What is intrinsic activity?

A

Intrinsic activity or efficacy refers to the relative ability of a drug-receptor complex to produce a maximum functional response

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12
Q

What is functional antagonism?

A

An antagonist may act at a completely separate receptor, initiating effects that are functionally the opposite of the agonist.

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13
Q

What is a competitive antagonist?

A

A competitive antagonist is a receptor antagonist that binds to a receptor but does not activate the receptor.

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14
Q

What is a non-competitive antagonist?

A

A non-competitive antagonist binds to an allosteric site on the receptor to prevent activation of the receptor

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15
Q

What is the equation for molarity?

A

Molarity(M) = g/L
——
MWt

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16
Q

Why do we need to consider drug concentrations in molarity, as opposed to weight?

A

Different concentrations of molecules and this is critical in determining drug action

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17
Q

What is drug binding governed by?

A

Association and dissociation

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18
Q

What does an agonist binding to a receptor cause?

A

Conformational change

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19
Q

What do agonists have compared to antagonists?

A

Agonists have intrinsic efficacy (can activate receptor) and efficacy (cause measurable response) while antagonists have affinity only (cannot activate receptor)

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20
Q

Why don’t antagonists cause a response?

A

They lack intrinsic efficacy

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21
Q

How do we measure drug-receptor interactions by binding?

A

Binding a radioactively labelled liand to cells o membranes prepared from cells.

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22
Q

What is Bmax?

A

Maximum binding capacity - no receptors left

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23
Q

What is Kd?

A

Concentration of ligand required to occupy 50% of the available receptors

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24
Q

What does a lower Kd value mean in terms of affinity?

A

Lower value = higher affinity

Kd is actually the reciprocal of affinity

25
Q

If drug A has a Kd of 1nM and drug B has a Kd of 1mM, which has higher affinity?

A

Drug A - lower concentration required occupy 50% of receptors

26
Q

When the concentration of a drug is expressed linearly, what is the shape of the graph showing the relationship between [drug] and proportion of bound receptors?

A

Rectangular hyperbola

27
Q

When the concentration of a drug is expressed logarithmically, what is the shape of the graph showing the relationship between [drug] and proportion of bound receptors?

A

Sigmoidal

28
Q

For example, what is -9(log10)M?

A

10^-9 M

29
Q

What could the response generated by a drug be?

A

Change in signalling pathway, change in cell or tissue behaviour (e.g. Contraction)

30
Q

What is EC50?

A

Effective concentration giving 50% of maximal response

31
Q

What is EC50 a measure of?

A

Potency

32
Q

How does dose differ from concentration?

A

Concentration = known concentration at site of action

Dose = concentration at site of action is unknown eg dose to a patient in mg or mg/kg

33
Q

What does a ligand require to have potency?

A

1) ligand binding to the receptor (affinity)
2) receptor activation (intrinsic efficacy)
3) things to happen to generate a measurable response

Affinity + efficacy = potency

34
Q

Why do you need selective/specific activation of b2 adrenoceptors in the airways to treat asthma?

A

Other b-adrenoceptors such as b1 in the heart which would increase force and rate

35
Q

What is the Kd of b1 adrenoceptors to salbutamol as apposed to b2 adrenoceptors and what does this mean?

A

B1 Kd - 20 micromoles
B2 Kd - 1 micromole

B2 receptors have a lower Kd (20 fold) so a higher affinity.

36
Q

How is salbutamol usage enhanced?

A

By b2 selective efficacy and route of administration

37
Q

What is the Kd of b1 and b2 adrenoceptors to salmeterol and what does this mean?

A

B1 Kd - 1900nM
B2 Kd - 0.55 nM

B2 lower Kd so higher affinity - very selective (3455 fold)

But no selective efficacy, selectivity based on affinity

38
Q

Why is response controlled or limited often?

A

Eg muscles can only contract so much, glands can only secrete so much

39
Q

In some cases <100% occupancy = 100% response. What is this due to?

A

Spare receptors

40
Q

When are spare receptors often seen?

A

When receptors catalytically active eg GPCRs or tyrosine kinase

41
Q

Why do spare receptors exist?

A
  • Amplification in the signal transduction pathway

- Response limited by a post-receptor event eg contraction

42
Q

For example, in the parasympathetic stimulation of M3 receptors, what percentage of receptors need to be occupied for maximal contraction of the airway smooth muscle?

A

10%

- so 90% appear to be spare receptors

43
Q

Why have spare receptors?

A

Increase sensitivity so allow responses at low concentrations of agonist

44
Q

Are receptor numbers fixed?

A

No

Tend to increase with low activity (up-regulation) and decrease with high activity (down-regulation [for drugs this can contribute to tolerance/tachyphylaxis])

45
Q

Why do partial agonists have lower intrinsic activity?

A

They have lower efficacy than full agonists

46
Q

What is the relevance of partial agonists?

A

They can allow a more controlled response, work in the absense of/low levels of ligand and act as an antagonist if there are high levels of full agonist

47
Q

What are examples of partial agonists?

A

Opiods - pain relief, recreational
Action through mu-opiod receptor
Can lead to death as respiratory depression

48
Q

Why can buprenorphine be adventageous to morphine in some clinical settings?

A

Heroin - full agonist, Buprenorphine - partial agonist

adequate pain control, less respiratory depression as lower Kd and lower efficacy

49
Q

Are partial agonists ALWAYS partial agonists?

A

No - compound and system dependent so increasing receptor number can change a partial agonist into a full agonist

50
Q

Do full or partial agonists have a lower efficacy?

A

Partial

51
Q

What is IC50?

A

Index of antagonist potency determined by strength of stimulus

52
Q

What is an example of a high affinity, competitive antagonist at mu-opiod receptors?

A

Naloxone - reversal of opioid mediated respiratory depression - high affinity means it will compete effectively with other opiods

53
Q

What are competitive antagonists also known as?

A

Surmountable angtagonists

54
Q

What shift in a graph do reversible competitive antagonists cause?

A

Parallel shift to the right of the agonists concentration-response curve

55
Q

What are irreversible competitive antagonists also known as?

A

Non-surmountable

56
Q

What shift in a graph do irreversible competitive antagonists cause?

A

Parallel shift to the right of the agonist concentration-response curve and at higher concentration suppress the maximal response

57
Q

What is an example of an irreversible competitive antagonist?

A

Phenoxybenzamine - non selective irreversible a1 blocker used in hypertension episodes in pheochromocytoma

Clopidogrel (plavix) - P2Y12 antagonist to reduce thrombosis/risk of heart disease - it is a prodrug so needs cytochrome P450 metabolism

58
Q

What do allosteric sites provide binding for?

A

Agonists

Moleculs that enhance or reduce effects of agonists (eg non competitive antagonism)

ESA1 - Physiology and Pharmacology (11 decks)

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